“Brain-body physiology: Local, reflex, and central communication”
Behavior is tightly synchronized with bodily physiology.
Internal needs from the body drive behavior selection, while optimal behavior performance requires a coordinated physiological response. Internal state is dynamically represented by the nervous system to influence mood and emotion, and body-brain signals also direct responses to external sensory cues, enabling the organism to adapt and pursue its goals within an ever-changing environment.
In this review, we examine the anatomy and function of the brain-body connection, manifested across local, reflex, and central regulation levels. We explore these hierarchical loops in the context of the immune system, specifically through the lens of immunoception, and discuss the impact of its dysregulation on human health.
These levels form control loops, with higher levels regulating lower ones to achieve adaptive bodily control.
Top: central, adaptive regulation, and immunoception involve higher-order brain structures integrating interoceptive information with external sensory data, past experiences, motivational drives, and emotions to form a complex representation. This integration allows adaptive modulation of the internal physiological state, including of the immune system, across different contexts and timescales, enabling prospective and goal-directed regulation of physiology. This regulation includes adjusting the homeostatic set points and modulating body phyisiology directly and indirectly through adjustments in motivation and behavior. Adaptive control is guided by cortical regions (darker blue) such as the aIC, ACC, vmPFC, and OFC, while subcortical regions (lighter blue) like the CeA, BNST, hypothalamus, VS, PAG, and PBN implement the integrated adjustments in physiology, motivation, and behavior.
Middle: reflexive control is a quick, reactive system that integrates at subcortical sites (green), such as the hypothalamus or the NTS and AP in the brainstem. Here, current bodily state information is compared to predefined homeostatic set points, and if a deviation is sensed, hard-wired responses regulate physiology to return to its set point, such as during inflammation. The autonomic nerves, including the sympathetic and parasympathetic branches, carry instructions from the brain and exert differential effects on inflammation.
Bottom: local modulation occurs in a bidirectional manner between sensory neurons innervating peripheral sites and local cells, including immune cells. These interactions influence inflammation by modulating cytokine or neuropeptide secretion (right side). aIC, anterior insular cortex; ACC, anterior cingulate cortex; vmPFC, ventromedial prefrontal cortex; OFC, orbitofrontal cortex; CeA, central nucleus of the amygdala; BNST, bed nucleus of the stria terminalis; VS, ventral striatum; PAG, periaqueductal gray; PBN, parabrachial nucleus; NTS, nucleus of the solitary tract; AP, area postrema.
The segregation between the brain and the body that has come to dominate modern medicine is motivated by the need to understand the causal mechanisms of physiological phenomena. It required dissecting the underpinning of each physiological system in isolation to gain a detailed understanding of its components. This contrasts with Eastern medical practices, which are governed by an integrated mind-body perception. However, modern science and medicine have reached a point in which emerging evidence in fields ranging from immunology, reproduction, cardiovascular disease, microbiology, and others highlights the relevance of interconnections between these systems. In seeking to reunite our understanding of the brain and body, science has provided evidence for interactions between the nervous system and other physiological systems at multiple levels of interaction. We will define these interactions as a set of hierarchical loops: local, reflexive, and central. This conceptual segregation, although artificial, will allow us to discuss each loop with its own set of parameters and specific regulation and to define how they synchronize in the overall scheme of brain-body integration. Finally, we will exemplify how these concepts apply to the interaction of the brain with one essential peripheral system, the immune system, and the concept of immunoception.
The vagus nerve collectively innervates a variety of organs in the gut as well as the airways (lungs, trachea, and larynx), vasculature (heart, arteries), and other abdominal and thoracic sites. Vagal sensory neurons include first-order sensors that directly sense stimuli, as well as second-order neurons that receive inputs from upstream sentinel cells like enteroendocrine cells in the intestine, glomus cells in the vasculature, neuroepithelial bodies in the lung, taste cells in the larynx, and immune cells Some are chemosensory neurons, specialized to detect hypoxic or hypercapnic conditions, ingestion of nutrients or nausea-inducing toxins, inhalation of certain cough-inducing irritants, or infection by sickness-causing pathogens. Others are mechanosensory neurons that detect changes in blood pressure or blood volume, airway closure, and stretch of organs like the lungs, stomach, heart, esophagus, and intestine. Single-cell atlases of vagal sensory neurons revealed incredible cell diversity, with dozens of distinct cell types, far more than the number of known vagal reflexes. Furthermore, genetic and anatomical mapping approaches revealed many vagal terminal morphologies with unknown sensory properties. Thus, there are additional capabilities of the vagus nerve that await characterization.
Central regulation and immunoception
Local and reflexive levels of control provide fast and direct reactive regulation of bodily physiology through hard-wired action programs. Higher-order brain areas act more adaptively, synchronizing changes across physiological systems and timescales, adjusting bodily functions in real time during behavior, and proactively initiating central regulatory actions. They integrate information about the current state of different bodily systems and environmental conditions with evolutionarily selected programs, prior experience, and motivational state. This processing enables the brain to anticipate future states and adjust bodily functions to meet incoming needs or challenges. To achieve such adjustments, higher-order brain areas exert top-down control of physiology, including temporary alterations of the homeostatic set points to accommodate expected states, as well as of motivational drives and behavior. Central circuits of the interoceptive nervous system are thus essential for adapting body physiology in dynamic environments. Emerging theories propose that adaptive homeostasis is central to brain function and provide working models for interoception and bodily regulation.
These pathways converge in the NTS and PBN, ascend via the thalamus (e.g., ventromedial and ventroposterior lateral nuclei), and reach cortical areas such as the posterior IC, ACC, S1, and S2. Humoral information detected by CVOs (e.g., IL-6) is also transmitted through neural pathways to higher brain regions. Visceromotor cortices, including the aIC, ACC, vmPFC, and OFC, mediate the contextual and adaptive regulation of physiology, initiating coordinated responses across physiological systems and behavior. These responses are recruited by interconnected subcortical structures, with the hypothalamus (e.g., PVN and LHA) playing a crucial role in sensing physiological needs and mediating homeostatic control by engaging autonomic, neuroendocrine, immune, and motivated behavioral responses as needed. The CeA and BNST are involved in processing emotions and stress and in recruiting the physiological responses associated with their expression. Additional regions contributing to adaptive physiological changes include the VS and VTA, which process reward and motivation, the PAG, which coordinates integrated behavioral-autonomic responses, and autonomic nuclei such as the DMV and VLM. Central bodily regulation among these and other brain regions involves numerous feedforward and feedback modulatory connections across different levels of the neural hierarchy to process and control the internal physiological state. Abbreviations in violet correspond to brain regions located deeper in the brain with respect to the views provided in the illustration. NTS, nucleus of the solitary tract; AP, area postrema; PBN, parabrachial nucleus; PAG, periaqueductal gray; TH, thalamus; IC, insular cortex; S1, primary somatosensory cortex; S2, secondary somatosensory cortex; OFC, orbitofrontal cortex; VLM, ventrolateral medulla; DMV, dorsal motor nucleus of the vagus; CeA, central nucleus of the amygdala; VTA, ventral tegmental area; HT, hypothalamus; PVN, paraventricular nucleus of the hypothalamus; LHA, lateral hypothalamic area; BNST, bed nucleus of the stria terminalis; VS, ventral striatum; ACC, anterior cingulate cortex; vmPFC, ventromedial prefrontal cortex.
The nervous system pervades every organ and tissue in the body, providing an extraordinary capability for integrating information, eliciting rapid responses, and anticipating specific experiences.
This intricate system enables the organism to operate cohesively.
Despite our growing knowledge, we are still only at the threshold of understanding the complex mechanisms at play. Ongoing research promises to unveil new facets of physiology and may provide insights into conditions often regarded as psychosomatic. It is a common misconception to trivialize these conditions as being “all in your head,” yet it is increasingly clear that the brain’s activities resonate throughout the entire organism. What transpires within the neural confines has systemic repercussions, challenging us to broaden our perspective on health and disease.
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